Process for the preparation of 4-(8-chloro-5 6-dihydro-11h-benzo-(5 6)-cyclohepta-(1 2b)-pyridin-11-ylidene-1-piperidiniecarboxylic acid ethyl ester (loratadine)

ABSTRACT

A process and new oxazolinic intermediates for the preparation of 4-(8-chloro-5,6-dihydro-11H-benzo-[5,6]-clohepta-[1,2-b]-pyridin-11-ylidene)-1-piperidinecarboxylic acid ethyl ester (loratadine) is described. The process starts from 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methyl-pyridine, a new intermediate to obtain loratadine. 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methyl-pyridine is condensed with 3-chloro-benzyl-chloride and the resultant product is treated with Grignard reagent of 4-chloro-N-methyl-piperidine. [3-(2-(3-chloro-phenyl)-ethyl]-pyridin-2-yl]-1-(methyl-piperidin-4-yl)-methanone is obtained for subsequent hydrolysis. Starting from this last compound it is possible to obtain loratadine with known methods.

The present invention relates to a process for preparing loratadine, amedicinal product with antihistamine activity. Loratadine is ethyl4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate(The Merck Index, 12th ed., 5608, p. 953). More specifically, theinvention relates to a process for synthesizing loratadine from a novelintermediate, 2-(4,4-dimethyl4,5-dihydrooxazol-2-yl)-3-methylpyridine.

Loratadine was described for the first time in Schering patent U.S. Pat.No. 4,282,233. In the said patent, the synthesis of loratadine isdescribed starting with 8-chloro-I1-(1-methylpiperid-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridinea), which reacts with ethyl chloroformate in benzene. Scheme 1illustrates the reaction.

From examination of the patent literature pertaining to the synthesis ofloratadine, it is found that there are two main intermediates via whichcompound a) is obtained. The first is[3-[2-(3-chlorophenyl)ethyl]-pyridin-2-yl]-(1-methyl4-piperidyl)methanoneof formula b), and the second is8-chloro-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]-pyridin-11-one offormula c).

Schering patent U.S. Pat. No. 4,731,447 describes the synthesis ofcompound a) from compound b), the latter compound being obtained from3-methyl-2-cyanopyridine in four steps. Compound b) gives compound a) bycyclization with a superacid having a Hammett acidity constant lowerthan −12. U.S. Pat. No. 4.731.447 in turn describes the synthesis ofcompound c) from 3-[2-(3-chlorophenyl)ethyl]-2-pyridinecar-boxamide, ina single step, by treatment with a superacid, or in three steps withoutthe use of a superacid.

However, given their chemical corrosiveness, superacids are problematicto use industrially. The synthesis of a) from compound c) is describedin Schering U.S. Pat. No. 4,659,716. a) is obtained by reacting compoundc) with the Grignard reagent of 4-chloro-N-methylpiperdine, to give8-chloro-11-(1-methyl-piperidin4-yl)-6,11-dihydro-5H-benzo-[5,6]cyclohepta[1,2-b]pyridin-11-ol,which, by subsequent dehydration, gives a). Another process thatinvolves starting with compound c) and obtaining loratadine withoutproceeding via compound a) is described in Schering patent applicationWO 00/37457. In this case, the synthesis proceeds via a Wittig reactionbetween compound c) and a phosphorus ylide; the reaction generates anunstable “β-hydroxyphosphonate” intermediate. On account of itsinstability, the intermediate “β-hydroxyphosphonate” needs to bestabilized by adding a protonating agent (water or acetic acid) and onlythereafter, by thermal decomposition it can give loratadine. However, asdescribed in WO 00/37457, the said product is not in pure form, butneeds to be purified several times by distillation and finallyrecrystallized to remove the impurities of solvent, of compound c) andof phosphorus-containing compounds. Thus, in addition to beinglaborious, this process also involves losses of product.

The syntheses described hitherto therefore involve various drawbacksincluding a large number of steps, the use of reagents that aredifficult to handle at the industrial level, the formation of unwantedside-reaction products and therefore reactions to purify the product orthe intermediate, which reduce the yields.

Surprisingly, a process that represents one of the aspects of thepresent invention has now been found, this process making it possible tosynthesize loratadine from2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine of formula I.

Compound I reacts with 3-chlorobenzyl chloride in the presence of astrong base to give the compound of formula II.

Compound II, reacting in the presence of the Grignard reagent of4-chloro-N-methylpiperidine in an inert solvent, gives compound IIIaccompanied by small amounts of compound VI.

Compound III, along with compound VI which may be present, is thenconverted under hydrolytic conditions into the intermediate b) andfinally from the said intermediate into loratadine by known methods.

Scheme 2 compares the process that is the object of the presentinvention with the processes described by Schering, indicated by theabbreviations Z, S1 and S2, respectively.

A second aspect of the present invention is represented by the novelcompounds of formulae I, II and III and their use for the preparation ofloratadine.

A third aspect is represented by a process for obtaining theintermediate b) from compound I, which, by treatment with lithiumdiisopropylamide (LDA) at 0° C. and then with 3-chlorobenzyl chloride,gives compound II. Subsequent treatment of compound II with the Grignardreagent of 4-chloro-N-methylpiperidine produces compound III, which, onhydrolysis, gives the intermediate b).

A fourth aspect of the invention is represented by an alternativemethod, relative to processes S1 and S2 of scheme 2, for obtaining theintermediate c) from compound II, which is hydrolysed to give3-[2-(3-chlorophenyl)ethyl]-pyridine-2-carboxylic acid of formula IV.

The acid function of compound IV is converted into the correspondingacid chloride and then coupled via a Friedel-Crafts reaction to give theintermediate c).

A fifth aspect of the present invention is a process for synthesizingloratadine by preparation of compound II to give c) according to theprocess described above, followed by conversion of c) into loratadineaccording to known techniques.

A preferred embodiment of the invention consists in using2-(4,4-dimethyl4,5-dihydrooxazol-2-yl)-3-methylpyridine of formula I asstarting compound.

Obviously, the use of oxazoline analogues such as the 4-methyl-,4,4-diethyl- or 4-ethyloxazoline, bearing the same substituent inposition 2, fall within the spirit of the present invention. The choiceof the 4,4-dimethyloxazoline (compound I) is based solely on criteria ofprocess economics.

The route that has been found to be the most advantageous for obtainingcompound I is that described in the article by Fryzuk M. D., JafarpourL. and Rettig S. J., Tetrahedron: Asyinmetry, 1998, 9, 3191. Theexperimental conditions for obtaining2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine were drawn fromthis article. The latter compound is obtained by reaction between2-cyano-3-methylpyridine and 1,1-dimethylaminoethanol, using anhydrousZnCl₂ as catalyst at 140° C. for 15 hours, in the absence of solvent.

Compound I thus obtained was reacted with 3-chlorobenzyl chloride or ananalogue thereof (see scheme 3) in the presence of a strong base,preferably lithium diisopropylamide (LDA). The reaction was performed inan inert solvent (THF, toluene, diethyl ether or hexane);tetrahydrofuran (THF) and a temperature range of between −15° C. and 25°C. and preferably between −5° C. and +5° C. are particularly preferred,giving3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridineof formula II.

By reacting compound II with the Grignard reagent of4-chloro-N-methylpiperidine, prepared according to standard techniques,in THF and at a temperature of between −40° C. and 0° C. and preferablybetween −20° C. and −10° C.,[3-[2-(3-chlorophenyl)ethyl]-2-[4,4-dimethyl-2-(1-methyl-piperidin4-yl)-oxazolidin-2-yl]-pyridi-neof formula III is obtained.

Addition of the Grignard reagent to compound II takes place selectivelyand therefore, as is seen in scheme 2, an additional step is avoided,which is, however, necessary by the Schering process S1.

Finally, compound III may be converted into b) by hydrolysis, andloratadine is obtained from this product according to known techniques.

The following experimental examples are now given for the purposes ofillustrating the invention more clearly, without, however, limiting it.

EXAMPLE 1 Synthesis of2-(4,4dimethyl4,5-dihydrooxazol-2-yl)-3-methylpyridine

100 g (0.847 mol) of 3-methyl-2-cyanopyridine, 151.08 g (1.695 mol) of2-methyl-2-aminopropanol and 5.77 g of anhydrous ZnCl₂ (0.042 mol) areplaced in a 300 ml jacketed reactor, the temperature is raised to 140°C. (at about 60° C. a solution is obtained) and is maintained at 140° C.for 15-18 hours. During the reaction, ammonia vapours are evolved, andare collected in a trap of dilute hydrochloric acid. The end of thereaction is monitored by TLC. At the end of the reaction the mixture iscooled to 60° C. and, at this point, it is filtered through a Goochcrucible to give about 190.06 g of white salts. Cooling is thencontinued to room temperature. 250 g of toluene and 99 g of saturatedNaCl solution are added. The aqueous phase is re-extracted with tolueneand the organic phases are combined and then washed again, thus removingthe unreacted dimethylaminoethanol. The toluene solution is evaporatedto give 166.5 g of a pale red oil with an HPLC titre of compound I of95.3%, the remainder consisting of the compound of formula V.

Compound V may in turn be converted into the oxazoline by treatment withmesyl chloride and triethylamine in CH₂Cl₂ at −5° C.

Compound I may also be distilled at 105-112° C. and at 1.5 mmHg to givean oxazoline titre>97%. Yield 98.5%

Compound I: ¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.52 (dd, J=4.3 and 1.8 Hz,1 H); 7.57 (dd, J=7.9 and 1.8 Hz, 1 H); 7.25 (dd, J=7.9 and 4.3 Hz, 1H);4.14 (s, 2 H); 2.59 (s, 3 H); 1.42 (s, 6 H).

EXAMPLE 2 Synthesis of3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-pyridine

521.7 ml of anhydrous THF and 521.7 ml of 2M LDA solution (1.04 mol) areplaced in a 3-litre jacketed reactor equipped with a mechanical stirrerand thermometer, and maintained under a nitrogen atmosphere, theinternal temperature is brought to −5° C. and a solution consisting of158.8 g of oxazoline (0.835 mol) and 834.7 ml of anhydrous THF is thenadded slowly, keeping the temperature at about 0° C. After adding a fewdrops of solution, a strong blue-violet colour is obtained. The totaladdition time is about one hour. 154.6 g (0.96 mol) of 3chlorobenzylchloride are then added over about 1.5 hours, while still maintainingthe temperature at 0° C. At the end of the reaction, 521.7 g of waterare added while bringing the temperature to 20-25° C. The two phases arethen separated and the organic phase is evaporated to give an oil. Thecrude product thus obtained is taken up in toluene and filtered throughTonsil. The filtrate is concentrated to give 268.1 g of an oil with anHPLC titre of 79%. 91.8% conversion, yield=80.2%

¹H-NMR (200 MHz, CDCl₃) δ (ppm): 8.58 (dd, 1 H); 7.31-7.10 (m, 5 H);4.17 (s, 2 H); 3.37-3.28 (m, 2 H); 2.95-2.86 (m, 2 H); 1.47 (s, 6 H)

¹³C-NMR (50 MHz, CDCl₃) δ (ppm): 160.78 (s); 147.75 (d); 146.07 (s);144.10 (s); 139.22 (d); 138.52 (s); 134.44 (s); 129.98 (d); 129.11 (d);127.07 (d); 126.61 (d); 125.22 (d); 79.02 (t); 69.07 (s); 37.37 (t);35.84 (t); 28.98 (q, two coincident methyls).

EXAMPLE 3 Synthesis of[3-[2-(3-chlorophenyl)ethyl]-2-[4,4-dimethyl-2-(1-methyl-piperidin-4yl-oxazolidin-2-yl]pyridine

Preparation of the Grignard Reagent

10 g of magnesium filings (0.41 mol) and 163 g of anhydrous THF areplaced in a 400 ml reactor equipped with a mechanical stirrer, a bubblecondenser, a thermometer and a 100 ml dropping funnel, under a nitrogenatmosphere. The system is brought to 60° C. and about 1 ml of Vitride®(70% w/w solution of sodium dihydrobis(2-methoxyethoxy)aluminate intoluene) and about 5% of the solution of 4-chloro-N-methylpiperidine(57.7 g, 0.41 mol) in 163 g of anhydrous THF are added. After a fewminutes, a gentle exothermicity is noted. The remainder of the solutionis then added slowly. Once the addition is complete, the reactionmixture is maintained at 60° C. overnight. The Grignard suspension,which is easily stirrable, is used without further modification in thesubsequent coupling stage.

Coupling

116 g of crude3-[2-(3-chlorophenyl)ethyl]-2-(4,4dimethyl-4,5-dihydrooxazol-2-yl)pyridine(0.32 mol) and 368.6 g of anhydrous THF are placed in a 1-litre reactorequipped with a mechanical stirrer, a thermometer and a 500 ml droppingfunnel, under a nitrogen atmosphere. The solution is cooled to −20° C.Addition of the Grignard reagent prepared in the preceding stage is thenstarted, while keeping the temperature at about −20° C. Next the coolingis stopped and the system is allowed to return to room temperature. Thereaction progress is followed by HPLC. After leaving overnight at roomtemperature, the HPLC monitoring shows about 2.9% (by area) of unreacted3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridine.The mixture is diluted with toluene (200 ml) and 270 g of acetic acid(aqueous 10% w/w solution) are added slowly. The resulting mixture isstirred for about 30 minutes and then left to stand for a further 30minutes. The phases are separated. The organic phase gives 146 g of acrude product, in the form of a dark oil, consisting of a mixture ofcompound III and a small amount of compound VI. The mixture of the twoproducts is used in the subsequent reaction without furtherpurification.

EXAMPLE 4 Synthesis of[3-[2-(3-chlorophenyl)ethyl]-2-pyridyl](1-methyl-4-piperidyl)methanone

24.1 g of crude product obtained from the reaction of Example 3, 51.4 gof H₂O and 10.2 g of HCl (31% w/w) are placed in a 250 ml round-bottomedflask equipped with a magnetic stirrer and a bubble condenser. Thesolution thus obtained is brought to reflux. After refluxing for 14hours, the TLC and ¹H-NMR controls indicate the disappearance of thesubstrate. The mixture is cooled to room temperature, diluted withdichloromethane (CH₂Cl₂) (50 ml) and sodium hydroxide (NaOH) (30% w/w)is added up to pH=8.5-9. The organic phase is dried over sodium sulphate(Na₂SO₄) and the solvent is evaporated off under vacuum. The crudeproduct, in the form of a dark oil, is analysed by HPLC (area about58%). The ketone may be crystallized from H₂O in the form of thehydrochloride.

EXAMPLE 5 Synthesis of 3-[2-(3-chlorophenyl)ethyl]-pyridine-2-carboxylicacid

268.1 g (0.67 mol) of compound II and 645.6 g of H₂O are placed in a2-litre reactor equipped with a mechanical stirrer, at room temperature.787.3 g of 31% HCl are added to this dispersion. The resulting mixtureis then brought to reflux and left for at least 8 hours. The reaction ismonitored by TLC. At the end of the reaction, the mixture is cooled to60° C., 1340.6 g of toluene are added, the mixture is brought to aboutpH 5 with 30% NaOH, and the phases are separated. The aqueous phase isre-extracted with toluene, the two organic phases are combined and thetoluene is evaporated off to give 219 g of a dark oil with a titre of80%. A solid white product may be obtained from this oil bycrystallization from toluene at 0° C.

EXAMPLE 6 Synthesis of8-chloro-5,6-dihydrobenzo[5,6]cylcohepta[1,2-b]pyrid-11-one

5 g of compound IV with a titre of 70% are placed in a 250 ml reactor,70 g of SOCl₂ are added dropwise at room temperature and the mixture isbrought to 55-60° C. and left to react for three hours. Thedisappearance of the acid is monitored by TLC and the excess SOCl₂ isthen distilled off to give 6 g of a dark residue. This residue isdissolved in about 10 ml of dichloroethane, the reaction mixture iscooled to 0° C. and 5.3 g of AlCl₃ are then added portionwise. Theresulting mixture is then left overnight at between −5° C. and 0° C. Atthe end of the reaction, the mixture is acidified with 1N HCl, whilekeeping the temperature between 10-15° C., the phases are separated, asecond acidic extraction is carried out with 50 ml of water and theaqueous phases are combined and basified with NaOH to pH 12, and thenre-extracted with toluene. After evaporating off the solvent, a solid isobtained, which, when crystallized from diisopropyl ether, gives 2 g ofa pale yellow solid with an NMR titre>99%, 62% yield.

1. Process for synthesizing loratadine, which consists in a) reacting 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine of formula I

with 3-chlorobenzyl chloride, in the presence of a strong base, to give 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridine of formula II

b) reacting compound II with the Grignard reagent of 4-chloro-N-methylpiperidine, in an inert solvent, to give [3-[2-(3-chlorophenyl)ethyl]-2-[4,4-dimethyl-2-(1-methyl-piperidin-4-yl)-oxazolidin-2-yl]pyridine of formula III

c) hydrolysing compound III to give the intermediate of formula b)

which is converted by known methods into loratadine.
 2. Process according to claim 1, in which the strong base is preferably lithium diisopropylamide.
 3. Process according to claim 1, in which the inert solvent is preferably tetrahydrofuran.
 4. Process for synthesizing the intermediate b), which consists in a) reacting 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine of formula I

with 3-chlorobenzyl chloride, in the presence of a strong base, to give 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridine of formula II

b) reacting compound II with the Grignard reagent of 4-chloro-N-methylpiperidine, in an inert solvent, to give [3-[2-(3-chlorophenyl)ethyl]-2-[4,4-dimethyl-2-(1-methyl-piperidin-4-yl)-oxazolidin-2-yl]pyridine of formula III

c) hydrolysing compound m to give the intermediate of formula b)


5. Process according to claim 4, in which the solvent is preferably tetrahydrofuran, while the strong base is preferably lithium diisopropylamide.
 6. Process according to claim 4, in which the hydrolysis is preferably performed in acidic medium.
 7. Process for synthesizing the intermediate c), which consists in

a) reacting 2-(4,4-dimethyl4,5dihydrooxazol-2-yl)-3-methylpyridine of formula I

with 3-chlorobenzyl chloride, in the presence of a strong base, to give 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)pyridine of formula II

b) hydrolysing the oxazoline group of the compound of formula II to give 3-[2-(3-chlorophenyl)ethyl]-2-pyridinecarboxylic acid of formula IV

c) converting the compound of formula IV into the corresponding acid chloride and subsequently condensation to give compound c) via a Friedel-Crafts reaction.


8. Process according to claim 5, in which the solvent is preferably tetrahydrofuran, while the strong base is preferably lithium diisopropylamide.
 9. Process according to claim 5, in which the hydrolysis is preferably performed in acidic medium.
 10. Compound chosen from a) 2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-3-methylpyridine of formula I

b) 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl4,5-dihydrooxazol-2-yl)pyridine of formula II

c) 3-[2-(3-chlorophenyl)ethyl]-2-[4,4-dimethyl-2-(1-methyl-4-piperidyl)-2-oxazolidinyl]pyridine of formula III


11. Use of a compound chosen from a) 2-(4,4-dimethyl4,5-dihydrooxazol-2-yl)-3-methylpyridine of formula I b) 3-[2-(3-chlorophenyl)ethyl]-2-(4,4-dimethyl-4,5dihydrooxazol-2-yl)pyridine of formula II c) 3-[2-(3-chlorophenyl)ethyl]-2-[4,4-dimethyl-2-(1-methyl-4-piperidyl)-oxazolidin-2-yl]pyridine of formula III for the preparation of loratadine. 